Skip to main content

First-in-human phase 1/2a trial of CRLX101, a cyclodextrin-containing polymer-camptothecin nanopharmaceutical in patients with advanced solid tumor malignancies


Patients with advanced solid malignancies were enrolled to an open-label, single-arm, dose-escalation study, in which CRLX101 was administered intravenously over 60 min among two dosing schedules, initially weekly at 6, 12, and 18 mg/m2 and later bi-weekly at 12, 15, and 18 mg/m2. The maximum tolerated dose (MTD) was determined at 15 mg/m2 bi-weekly, and an expansion phase 2a study was completed. Patient samples were obtained for pharmacokinetic (PK) and pharmacodynamic (PD) assessments. Response was evaluated per RECIST criteria v1.0 every 8 weeks. Sixty-two patients (31 male; median age 63 years, range 39–79) received treatment. Bi-weekly dosing was generally well tolerated with myelosuppression being the dose-limiting toxicity. Among all phase 1/2a patients receiving the MTD (n = 44), most common grade 3/4 adverse events were neutropenia and fatigue. Evidence of systemic plasma exposure to both the polymer-conjugated and unconjugated CPT was observed in all treated patients. Mean elimination unconjugated CPT Tmax values ranged from 17.7 to 24.5 h, and maximum plasma concentrations and areas under the curve were generally proportional to dose for both polymer-conjugated and unconjugated CPT. Best overall response was stable disease in 28 patients (64 %) treated at the MTD and 16 (73 %) of a subset of NSCLC patients. Median progression-free survival (PFS) for patients treated at the MTD was 3.7 months and for the subset of NSCLC patients was 4.4 months. These combined phase 1/2a data demonstrate encouraging safety, pharmacokinetic, and efficacy results. Multinational phase 2 clinical development of CRLX101 across multiple tumor types is ongoing.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6


  1. Gaur S, Chen L, Yen T et al (2012) Preclinical study of the cyclodextrin-polymer conjugate of camptothecin for the treatment of gastric cancer. Nanomedicine 8:721–730

    PubMed  Article  CAS  Google Scholar 

  2. Schluep T, Cheng J, Khin KT et al (2006) Pharmacokinetics and biodistribution of the camptothecin-polymer conjugate IT-101 in rats and tumor-bearing mice. Cancer Chemother Pharmacol 57:654–662

    PubMed  Article  CAS  Google Scholar 

  3. Pommier Y (2006) Topoisomerase I inhibitors: camptothecins and beyond. Nat Rev Cancer 6:789–802

    PubMed  Article  CAS  Google Scholar 

  4. Han Z, Wei W, Dunaway S et al (2002) Role of p21 in apoptosis and senescence of human colon cancer cells treated with camptothecin. J Biol Chem 277:17154–17160

    PubMed  Article  CAS  Google Scholar 

  5. Magrini R, Bhonde MR, Hanski ML et al (2002) Cellular effects of CPT-11 on colon carcinoma cells: dependence on p53 and hMLH1 status. Int J Cancer 101:23–31

    PubMed  Article  CAS  Google Scholar 

  6. Kummar S, Raffeld M, Juwara L et al (2011) Multihistology, target-driven pilot trial of oral topotecan as an inhibitor of hypoxia-inducible factor-1 alpha (HIF-1alpha) in advanced solid tumors. Clin Cancer Res 17:5123–5131

    PubMed  Article  CAS  Google Scholar 

  7. Lou JJ, Chua YL, Chew EH et al (2010) Inhibition of hypoxia-inducible factor-1 alpha (HIF-1alpha) protein synthesis by DNA damage inducing agents. PLoS One 5:e10522

    PubMed  Article  Google Scholar 

  8. Cheng J, Khin KT, Davis ME (2004) Antitumor activity of beta-cyclodextrin polymer-camptothecin conjugates. Mol Pharm 1:183–193

    PubMed  Article  CAS  Google Scholar 

  9. Cheng J, Khin KT, Jensen GS et al (2003) Synthesis of linear, beta-cyclodextrin-based polymers and their camptothecin conjugates. Bioconjug Chem 14:1007–1017

    PubMed  Article  CAS  Google Scholar 

  10. Davis ME (2009) Design and development of IT-101, a cyclodextrin-containing polymer conjugate of camptothecin. Adv Drug Deliv Rev 61:1189–1192

    PubMed  Article  CAS  Google Scholar 

  11. Jensen G, Hwang J, Schluep T (2008) Antitumor activity of IT-101, a cyclodextrin-containing polymer-camptothecin nanoparticle, in combination with various anticancer agents in human ovarian cancer xenografts. AACR Meeting Abstracts, p 767

  12. Numbenjapon T, Wang J, Colcher D et al (2009) Preclinical results of camptothecin-polymer conjugate (IT-101) in multiple human lymphoma xenograft models. Clin Cancer Res 15:4365–4373

    PubMed  Article  CAS  Google Scholar 

  13. Schluep T, Hwang J, Cheng J et al (2006) Preclinical efficacy of the camptothecin-polymer conjugate IT-101 in multiple cancer models. Clin Cancer Res 12:1606–1614

    PubMed  Article  CAS  Google Scholar 

  14. Schluep T, Hwang J, Hildebrandt IJ et al (2009) Pharmacokinetics and tumor dynamics of the nanoparticle IT-101 from PET imaging and tumor histological measurements. Proc Natl Acad Sci U S A 106:11394–11399

    PubMed  Article  CAS  Google Scholar 

  15. Svenson S, Wolfgang M, Hwang J et al (2011) Preclinical to clinical development of the novel camptothecin nanopharmaceutical CRLX101. J Control Release 153:49–55

    PubMed  Article  CAS  Google Scholar 

  16. Matsumura Y, Maeda H (1986) A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res 46:6387–6392

    PubMed  CAS  Google Scholar 

  17. Simon R, Freidlin B, Rubinstein L et al (1997) Accelerated titration designs for phase I clinical trials in oncology. J Natl Cancer Inst 89:1138–1147

    PubMed  Article  CAS  Google Scholar 

  18. Therasse P, Arbuck SG, Eisenhauer EA et al (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216

    PubMed  Article  CAS  Google Scholar 

  19. Minagawa Y, Kigawa J, Irie T et al (1997) Enhanced topoisomerase I activity and increased topoisomerase II alpha content in cisplatin-resistant cancer cell lines. Jpn J Cancer Res 88:1218–1223

    PubMed  Article  CAS  Google Scholar 

  20. Creaven PJ, Allen LM, Muggia FM (1972) Plasma camptothecin (NSC-100880) levels during a 5-day course of treatment: relation to dose and toxicity. Cancer Chemother Rep 56:573–578

    PubMed  CAS  Google Scholar 

  21. Muggia FM, Creaven PJ, Hansen HH et al (1972) Phase I clinical trial of weekly and daily treatment with camptothecin (NSC-100880): correlation with preclinical studies. Cancer Chemother Rep 56:515–521

    PubMed  CAS  Google Scholar 

  22. Ikegami T, Ha L, Arimori K et al (2002) Intestinal alkalization as a possible preventive mechanism in irinotecan (CPT-11)-induced diarrhea. Cancer Res 62:179–187

    PubMed  CAS  Google Scholar 

  23. Morris R, Munkarah A (2002) Alternate dosing schedules for topotecan in the treatment of recurrent ovarian cancer. Oncologist 7(Suppl 5):29–35

    PubMed  Article  CAS  Google Scholar 

  24. Schnipper LE, Smith TJ, Raghavan D et al (2012) American Society of Clinical Oncology identifies five key opportunities to improve care and reduce costs: the top five list for oncology. J Clin Oncol 30:1715–1724

    PubMed  Article  Google Scholar 

  25. Hochster H, Wadler S, Runowicz C et al (1999) Activity and pharmacodynamics of 21-Day topotecan infusion in patients with ovarian cancer previously treated with platinum-based chemotherapy. New York Gynecologic Oncology Group. J Clin Oncol 17:2553–2561

    PubMed  CAS  Google Scholar 

  26. Pommier Y (2004) Camptothecins and topoisomerase I: a foot in the door. Targeting the genome beyond topoisomerase I with camptothecins and novel anticancer drugs: importance of DNA replication, repair and cell cycle checkpoints. Curr Med Chem Anticancer Agents 4:429–434

    PubMed  Article  CAS  Google Scholar 

  27. Choi YJ, Rho JK, Lee SJ et al (2009) HIF-1alpha modulation by topoisomerase inhibitors in non-small cell lung cancer cell lines. J Cancer Res Clin Oncol 135:1047–1053

    PubMed  Article  CAS  Google Scholar 

Download references


The authors would like to thank all participating patients and their families, as well as the investigators, study coordinators, and operations staff. The authors also want to thank Dr. Marcia M. Miller and Dr. Mariana Tihova, Electron Microscopy Core; Dr. Shu Mi, Clinical Immunobiology Correlative Studies Laboratory (CICSL); and Yafan Wang, Translational Research Laboratory, City of Hope Comprehensive Cancer Center.

Acknowledgement of Research Support for the Study

Financial support for this study was provided by Cerulean Pharma, Inc., and by a grant from the National Cancer Institute (CA U54119347). Financial support for medical editorial assistance was provided by Cerulean Pharma, Inc.

Author Disclosures

DLK, EG, JH, JLR, and JJP are/were employees at Cerulean Pharma, Inc.

MED has stock in and is a paid consultant to Cerulean Pharma, Inc.

TS is a paid consultant for Cerulean Pharma, Inc. and employee at Calando Pharmaceuticals.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Yun Yen.

Additional information

Glen J. Weiss and Joseph Chao contributed equally to this work.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Weiss, G.J., Chao, J., Neidhart, J.D. et al. First-in-human phase 1/2a trial of CRLX101, a cyclodextrin-containing polymer-camptothecin nanopharmaceutical in patients with advanced solid tumor malignancies. Invest New Drugs 31, 986–1000 (2013).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


  • Nanopharmaceutical
  • Polymer conjugate camptothecin
  • Phase 1/2a
  • Solid tumor